Very rare HIV-1 infected individuals retain effective levels of CD4+ T cells and remain asymptomatic despite consistent viral loads greater than 104 or even 105 HIV-1 RNA copies/ml plasma. This extremely unusual, favorable response to HIV-1 infection remains incompletely characterized. Our initial study of three such viremic non-progressors (VNP) showed a lack of non-specific immune activation and consistent CD4+ T cell responses to HIV-1 despite the presence of replication competent, cytopathic R5 HIV-1. VNP therefore mimic the immune response of natural hosts of SIV that do not develop disease, including the sootey mangabey and African green monkey. Developing a detailed understanding of how these rare individuals remain healthy despite high HIV-1 load will be extremely useful in understanding the normal process of HIV-1 pathogenesis and in developing new treatments or vaccines for AIDS. We hypothesize that the VNP phenotype is caused by replication competent but weakly cytopathic HIV-1 or by effective immunity that maintains the mucosal barrier and prevents non-specific immune activation. To test this dual hypothesis we have three specific aims: 1. Isolate and characterize the replication and cytopathic effects of HIV-1 from VNP in PBMC and fetal thymic organ culture, 2. Characterize VNP PBMC subsets by immunophenotyping and cell sorting plus HIV-1 QPCR to discern whether immune subsets or the distribution of HIV-1 differ from other HIV-1 infected individuals, 3. Assay immune activation, serum LPS levels and soluble CD14 levels as well as specific HIV T cell responses in fresh PBMC from VNP compared with controls. PUBLIC HEALTH RELEVANCE: HIV Pathogenesis and Immunity in Viremic Non-Progressors Very rare HIV-1 infected individuals retain effective levels of CD4+ T cells and remain disease free despite consistent high viral. This extremely unusual, favorable response to HIV-1 infection remains incompletely characterized. Developing a detailed understanding of how these rare individuals remain healthy despite high HIV-1 load will be extremely useful in understanding the normal process of HIV-1 pathogenesis and in developing new treatments or vaccines for AIDS.